Pulmonary lymphangioleiomyomatosis (LAM), a rare progressive metastatic and potentially fatal interstitial lung disease, affects primarily women of childbearing age. Mutations of the Tuberous Sclerosis Complex 1 (TSC1) or TSC2 tumor suppressor genes induce LAM. LAM disease severity correlates with the degree of pathogenic lymphatic vessel density and serum levels of the pro-lymphangiogenic vascular endothelial growth factor-D (VEGF-D), a biomarker of LAM. VEGF-D signals by binding to VEGFR3 predominantly expressed on lymphatic endothelial cells (LECs) and myeloid-derived suppressor cells (MDSCs). Little is known, however, whether VEGF-D is merely a marker of LAM disease. Emerging concepts posit that the VEGF-D induces abnormal lymphangiogenesis and tumor invasion towards lymphatics. Tumors also employ active mechanisms of immune evasion by using immunosuppressive MDSCs. Because of the connection with VEGF-D being secreted by MDSCs, MDSCs infiltration correlates with lymphangiogenesis. This project centers on the hypothesis that in LAM, the TSC2-dependent upregulation of VEGF-D induces MDSC recruitment and abnormal lymphangiogenesis that modulate adaptive immunity by suppressing T cell function. Our observations also posits a translational hypothesis that pharmacological targeting of VEGFR3 signaling in LECs and MDSCs will abrogate abnormal lymphangiogenesis, and MDSC immunosuppressive function and will provide adjuvant therapy for preventing extracellular matrix remodeling and destruction of lung parenchyma in LAM. To test our hypothesis, we will specifically ask: In Aim 1: Does VEGF-D promote LAM cell invasiveness and abnormal lymphangiogenesis in LAM? In Aim 2: Do MDSCs induce immune suppression in LAM? and in Aim 3: Will therapeutic targeting of VEGF-D signaling in LECs and MDSCs be beneficial in abrogating the immunosuppressive function of MDSCs, abnormal lymphangiogenesis and lung destruction in LAM? In this project we suggest a new paradigm that MDSCs serve an immunomodulatory role in LAM. Collectively, our studies will impact basic and translational LAM research by: 1) determining mechanisms of immunosuppressive function of MDSCs; 2) defining a new role of lymphatic endothelium in regulating LAM cell invasiveness; and 3) providing insights about potential novel molecular targets and adjuvant therapeutics in LAM. Our study will also provide new insights and advance our understanding of immunobiology of LAM lesions, and may identify a major reason why abnormal lymphangiogenesis in LAM correlates with the disease severity, while complementing current treatments with immunotherapy to develop a cure for LAM.